Targeting cardiopulmonary calpains to mitigate toxicity of halogen gases.

制造工厂的意外泄漏是常见的，大量人群可能暴露于高浓度的 卤素（Cl 2/Br 2）浓度。使用卤素气体作为化学武器的情况也在增加。受害者 意外的溴接触会导致呼吸窘迫、心脏骤停和循环衰竭。研究 评估急性和慢性后遗症的溴接触是不够的，治疗仍然对症，因为没有 存在有效的对策。我们的研究已经证实，动物的心脏严重受损， 吸入高剂量卤素（Cl 2/Br 2）后存活。本申请的目的是识别生物 这些事件的责任机制，并制定适当的对策。基于令人兴奋的 初步数据表明，溴化反应物如溴化脂质是在肺中产生的。 溴化反应物/脂质随含氧血液沿着到达心脏。这些反应物非常重要 调节心跳的钙泵钙泵不活动导致钙积聚或 心脏细胞中的“钙超载”。钙超载是一个严重的问题，可导致心脏骤停， 死亡增加的钙也激活破坏性蛋白质，破坏心脏超微结构的钙蛋白酶。我们 因此，假设吸入Br 2会产生高活性中间体， 钙蛋白酶导致细胞骨架和线粒体损伤以及心肌功能障碍， 将减轻Br 2诱导的心肺功能障碍和死亡。这些假设将通过完成 这些实验的具体目标如下。SA #1：表征由以下因素诱导的心脏损伤和死亡 吸入溴化二氢。SA #2：检验Br 2和Br 2反应物激活心脏钙蛋白酶并导致 细胞骨架和线粒体损伤。SA#3：测试基于钙蛋白酶抑制剂的对策是否缓解 吸入溴引起的急性和慢性效应。该项目的结果将确定一种有效的解毒剂 加强对意外或故意接触溴引起的紧急情况的准备。

Accidental leaks from manufacturing plants are common and large groups of people may be exposed to high halogen (Cl2/Br2) concentrations. Use of halogen gases as chemical weapons is also on the rise. Victims of accidental bromine exposure experience respiratory distress, cardiac arrest and circulatory collapse. Studies evaluating acute and chronic sequelae of Br2 exposure are scant and treatment remains symptomatic as no effective countermeasures exist. Our studies have established that the heart is severely injured in animals that survive high dose halogen (Cl2/Br2) inhalation. The purpose of this application is to identify the biological mechanisms responsible for these events and develop appropriate countermeasures. Based on exciting preliminary data we propose that brominated reactants such as brominated lipids are produced in the lungs. Brominated reactants/lipids reach the heart along with oxygenated blood. These reactants inactivate important calcium pumps that regulate the heartbeats. Inactivity of calcium pumps causes calcium accumulation or “calcium overload” in the heart cells. Calcium overload is a serious problem and can lead to sudden cardiac death. Increased calcium also activates destructive proteins, the calpains that destroy cardiac ultrastructure. We therefore hypothesize that Br2 inhalation produces highly reactive intermediates that activate Ca2+ sensitive calpains leading to cytoskeletal and mitochondrial damage and myocardial dysfunction and that calpain inhibition will mitigate Br2-induced cardiopulmonary dysfunction and death. These hypotheses will be tested by completing the experiments outlined in the following specific aims. SA#1: Characterize cardiac injury and death induced by Br2 inhalation. SA#2: Test the hypothesis that Br2 and Br2 reactants activate cardiac calpains and cause cytoskeletal and mitochondrial damage. SA#3: Test whether calpain inhibitor based countermeasures mitigate acute and chronic effects caused by Br2 inhalation. The outcome from this project will identify an effective antidote for bromine toxicity and enhance readiness for emergencies arising from accidental or intentional exposures.